Project Summary/Abstract Melanocortin 4 Receptor Agonists for the Treatment of the Prader Willi Syndrome (PWS): Prader Willi syndrome (PWS) is an orphan disease with an incidence of 1/25,000-1/30,000 and a prevalence of about 25,000 patients in the USA. PWS patients exhibit intellectual disability, delayed growth, severe obesity and hyperphagia with absence of satiety, leading to significant morbidity and mortality. Due to uncontrolled food intake and food seeking behavior, care for PWS patients includes rigorous control of caloric intake. The genetics of PWS are complex, involving several imprinted genes on chromosome 15 that fail to be properly expressed. Important recent discoveries highlight a defect in one of these, the MAGEL2 gene, as one of the dominant contributors to PWS pathology. Defects in MAGEL2 in humans result in features of autism spectrum disorder, reduced intellectual ability and most aspects of behavior and metabolism associated with PWS [Schaaf et al. Nat Genet, 2013, 45(11), 1405]. Unraveling the function of the Magel2 gene resulted in the discovery that Magel2 deficient mice have functionally defective pro-opiomelanocortin (POMC) neurons. These neurons normally promote satiety by activating downstream melanocortin 4 receptors (MC4R). This inherent defect in POMC neurons can be bypassed and Magel2 deficient mice are responsive to therapeutic activation of the MC4R, resulting in control of appetite [Mercer et al. PLoS Genet, 2013, 9(1), e1003207]. This finding is important as the MC4R pathway is a key mediator in the control of satiety, energy metabolism and behavior in humans where MC4R loss-of-function mutations are associated with obesity with a reported prevalence of up to 5% in severe obesity. These findings provide the rationale for the treatment of PWS patients with an MC4R agonist. In preclinical studies, RM-493 administered to diet induced obese Rhesus monkeys elicited significant, ~ 13% weight loss over an 8 week treatment period. RM-493 was well tolerated and is without cardiovascular adverse effects. These findings have been replicated in Phase 1b, 4-week studies in humans, showing impressive weight loss. RM-493 has entered Phase II clinical trials for the treatment of general obesity. This grant proposes support for a Phase 2a, proof of concept, double-blind, placebo-controlled, randomized study in approximately 36 PWS patients for up to 10 weeks of treatment, to assess the effects of RM-493 on safety, weight reduction, and food-related behaviors. The data will provide critical support for a key GO-NO GO decision to proceed into larger and longer studies that would lead to a potential indication for the treatment of PWS patients.